TY - JOUR
T1 - A Missense Variant in PTPN22 is a Risk Factor for Drug-induced Liver Injury
AU - International DILI consortium (iDILIC)
AU - Drug-Induced Liver Injury Network (DILIN) investigators
AU - Cirulli, Elizabeth T.
AU - Nicoletti, Paola
AU - Abramson, Karen
AU - Andrade, Raul J.
AU - Bjornsson, Einar S.
AU - Chalasani, Naga
AU - Fontana, Robert J.
AU - Hallberg, P. r
AU - Li, Yi Ju
AU - Lucena, M. Isabel
AU - Long, Nanye
AU - Molokhia, Mariam
AU - Nelson, Matthew R.
AU - Odin, Joseph A.
AU - Pirmohamed, Munir
AU - Rafnar, Thorunn
AU - Serrano, Jose
AU - Stefánsson, K. ri
AU - Stolz, Andrew
AU - Daly, Ann K.
AU - Aithal, Guruprasad P.
AU - Watkins, Paul B.
AU - Bessone, Fernando
AU - Bjornsson, Einar
AU - Cascorbi, Ingolf
AU - Dillon, John F.
AU - Day, Christopher P.
AU - Hallberg, Par
AU - Hernández, Nelia
AU - Ibanez, Luisa
AU - Kullak-Ublick, Gerd A.
AU - Laitinen, Tarja
AU - Larrey, Dominique
AU - Maitland-van der Zee, Anke
AU - Martin, Jennifer H.
AU - Menzies, Dick
AU - Qin, Shengying
AU - Wadelius, Mia
AU - Aithal, Guruprasad P.
AU - Andrade, Raul J.
AU - Bessone, Fernando
AU - Bjornsson, Einar
AU - Cascorbi, Ingolf
AU - Daly, Ann K.
AU - Dillon, John F.
AU - Day, Christopher P.
AU - Hallberg, Par
AU - Hernández, Nelia
AU - Ibanez, Luisa
AU - Maitland-van der Zee, Anke
N1 - Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.
PY - 2019/5
Y1 - 2019/5
N2 - Background & Aims: We performed genetic analyses of a multiethnic cohort of patients with idiosyncratic drug-induced liver injury (DILI) to identify variants associated with susceptibility. Methods: We performed a genome-wide association study of 2048 individuals with DILI (cases) and 12,429 individuals without (controls). Our analysis included subjects of European (1806 cases and 10,397 controls), African American (133 cases and 1,314 controls), and Hispanic (109 cases and 718 controls) ancestry. We analyzed DNA from 113 Icelandic cases and 239,304 controls to validate our findings. Results: We associated idiosyncratic DILI with rs2476601, a nonsynonymous polymorphism that encodes a substitution of tryptophan with arginine in the protein tyrosine phosphatase, nonreceptor type 22 gene (PTPN22) (odds ratio [OR] 1.44; 95% confidence interval [CI] 1.28–1.62; P = 1.2 × 10 –9 and replicated the finding in the validation set (OR 1.48; 95% CI 1.09–1.99; P =.01). The minor allele frequency showed the same effect size (OR > 1) among ethnic groups. The strongest association was with amoxicillin and clavulanate-associated DILI in persons of European ancestry (OR 1.62; 95% CI 1.32–1.98; P = 4.0 × 10 –6 ; allele frequency = 13.3%), but the polymorphism was associated with DILI of other causes (OR 1.37; 95% CI 1.21–1.56; P = 1.5 × 10 –6 ; allele frequency = 11.5%). Among amoxicillin- and clavulanate-associated cases of European ancestry, rs2476601 doubled the risk for DILI among those with the HLA risk alleles A*02:01 and DRB1*15:01. Conclusions: In a genome-wide association study, we identified rs2476601 in PTPN22 as a non-HLA variant that associates with risk of liver injury caused by multiple drugs and validated our finding in a separate cohort. This variant has been associated with increased risk of autoimmune diseases, providing support for the concept that alterations in immune regulation contribute to idiosyncratic DILI.
AB - Background & Aims: We performed genetic analyses of a multiethnic cohort of patients with idiosyncratic drug-induced liver injury (DILI) to identify variants associated with susceptibility. Methods: We performed a genome-wide association study of 2048 individuals with DILI (cases) and 12,429 individuals without (controls). Our analysis included subjects of European (1806 cases and 10,397 controls), African American (133 cases and 1,314 controls), and Hispanic (109 cases and 718 controls) ancestry. We analyzed DNA from 113 Icelandic cases and 239,304 controls to validate our findings. Results: We associated idiosyncratic DILI with rs2476601, a nonsynonymous polymorphism that encodes a substitution of tryptophan with arginine in the protein tyrosine phosphatase, nonreceptor type 22 gene (PTPN22) (odds ratio [OR] 1.44; 95% confidence interval [CI] 1.28–1.62; P = 1.2 × 10 –9 and replicated the finding in the validation set (OR 1.48; 95% CI 1.09–1.99; P =.01). The minor allele frequency showed the same effect size (OR > 1) among ethnic groups. The strongest association was with amoxicillin and clavulanate-associated DILI in persons of European ancestry (OR 1.62; 95% CI 1.32–1.98; P = 4.0 × 10 –6 ; allele frequency = 13.3%), but the polymorphism was associated with DILI of other causes (OR 1.37; 95% CI 1.21–1.56; P = 1.5 × 10 –6 ; allele frequency = 11.5%). Among amoxicillin- and clavulanate-associated cases of European ancestry, rs2476601 doubled the risk for DILI among those with the HLA risk alleles A*02:01 and DRB1*15:01. Conclusions: In a genome-wide association study, we identified rs2476601 in PTPN22 as a non-HLA variant that associates with risk of liver injury caused by multiple drugs and validated our finding in a separate cohort. This variant has been associated with increased risk of autoimmune diseases, providing support for the concept that alterations in immune regulation contribute to idiosyncratic DILI.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85064320616&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/30664875
U2 - https://doi.org/10.1053/j.gastro.2019.01.034
DO - https://doi.org/10.1053/j.gastro.2019.01.034
M3 - Article
C2 - 30664875
SN - 0016-5085
VL - 156
SP - 1707-1716.e2
JO - Gastroenterology
JF - Gastroenterology
IS - 6
ER -